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Analysis of the mechanism of HBV reactivation mediated by SET protein

Research Project

Project/Area Number 21K07051
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 49060:Virology-related
Research InstitutionHamamatsu University School of Medicine

Principal Investigator

Ito Masahiko  浜松医科大学, 医学部, 助教 (50385423)

Project Period (FY) 2021-04-01 – 2024-03-31
Project Status Completed (Fiscal Year 2023)
Budget Amount *help
¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2023: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2022: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2021: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
KeywordsHBV / B型肝炎ウイルス / 潜伏感染 / HBV再活性化 / cccDNA / SET / 再活性化 / HBV cccDNA / HBVcccDNA
Outline of Research at the Start

HBVが肝細胞に感染すると核内でcccDNAが形成され、ウイルスRNAの発現やcccDNAレベルが亢進する。時間経過に伴いその発現レベルは低下し、潜伏感染状態へと移行する。このような潜伏感染状態の維持および再活性化に関するメカニズムについて、現在までまったく分かっていない。そこで本研究は、cccDNAの形成維持制御機構を明らかにすることで、HBV再活性化のメカニズムを解明する。

Outline of Final Research Achievements

Over one million individuals in Japan are estimated to be carriers of hepatitis B virus (HBV), and reactivation triggered by anticancer drugs and immunosuppressants poses a significant clinical issue. In this study, we identified SET as a novel cccDNA-binding protein and demonstrated that the downregulation of SET expression by specific drugs significantly enhances the levels of cccDNA and pgRNA. Additionally, we showed that SET interacts with histone H2AX, implicating its role in the formation of cccDNA from dslDNA. The results of this research not only contribute to understanding the mechanism by which SET regulates the maintenance of cccDNA but also lay the groundwork for the development of new therapeutic agents aimed at inhibiting cccDNA formation, eliminating latent cccDNA, and preventing HBV reactivation.

Academic Significance and Societal Importance of the Research Achievements

B型肝炎ウイルスのキャリアは、本邦にはおよそ100~120万人(人口1%)、世界にはおよそ4億人いることが知られている。キャリアにおけるHBV活性化の抑制や無症候性キャリアからの感染拡大の防止は急務となっている。本研究により明らかになったSETによるHBV cccDNA形成・維持・再活性化機構に関する知見は、cccDNAの形成阻害、潜伏感染したcccDNAの排除、再活性化の抑制するための薬剤の開発に繋がり、多くの患者を救うための治療法に発展する。

Report

(4 results)
  • 2023 Annual Research Report   Final Research Report ( PDF )
  • 2022 Research-status Report
  • 2021 Research-status Report
  • Research Products

    (16 results)

All 2024 2023 2022 2021

All Journal Article (8 results) (of which Int'l Joint Research: 2 results,  Peer Reviewed: 8 results,  Open Access: 4 results) Presentation (8 results) (of which Int'l Joint Research: 4 results)

  • [Journal Article] Impact of amino acid substitutions in hepatitis C virus core region on the severe oxidative stress.2024

    • Author(s)
      Takeshi Chida,Shinya Watanabe,Kazuyoshi Ohta,Hidenao Noritake,Masahiko Ito,Tetsuro Suzuki,Takafumi Suda,Kazuhito Kawata
    • Journal Title

      Free radical biology & medicine

      Volume: 212 Pages: 199-206

    • DOI

      10.1016/j.freeradbiomed.2023.12.014

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed
  • [Journal Article] SRPKIN-1 as an inhibitor against hepatitis B virus blocking the viral particle formation and the early step of the viral infection.2023

    • Author(s)
      Xiaofang Li,Kenji Nakashima,Masahiko Ito,Mami Matsuda,Takeshi Chida,Kazumasa Sekihara,Hirotaka Takahashi,Takanobu Kato,Tatsuya Sawasaki,Tetsuro Suzuki
    • Journal Title

      Antiviral research

      Volume: 220 Pages: 105756-105756

    • DOI

      10.1016/j.antiviral.2023.105756

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Oxidative stress sensor Keap1 recognizes HBx protein to activate the Nrf2/ARE signaling pathway, thereby inhibiting hepatitis B virus replication2023

    • Author(s)
      Ariffianto Adi、Deng Lin、Abe Takayuki、Matsui Chieko、Ito Masahiko、Ryo Akihide、Aly Hussein Hassan、Watashi Koichi、Suzuki Tetsuro、Mizokami Masashi、Matsuura Yoshiharu、Shoji Ikuo
    • Journal Title

      Journal of Virology

      Volume: 97 Issue: 10 Pages: 1-35

    • DOI

      10.1128/jvi.01287-23

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Role of hepcidin upregulation and proteolytic cleavage of ferroportin 1 in hepatitis C virus-induced iron accumulation2023

    • Author(s)
      Ohta Kazuyoshi、Ito Masahiko、Chida Takeshi、Nakashima Kenji、Sakai Satoshi、Kanegae Yumi、Kawasaki Hideya、Aoshima Takuya、Takabayashi Shuji、Takahashi Hirotaka、Kawata Kazuhito、Shoji Ikuo、Sawasaki Tatsuya、Suda Takafumi、Suzuki Tetsuro
    • Journal Title

      PLOS Pathogens

      Volume: 19 Issue: 8 Pages: e1011591-e1011591

    • DOI

      10.1371/journal.ppat.1011591

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Development and Use of a Kinetical and Real-Time Monitoring System to Analyze the Replication of Hepatitis C Virus2022

    • Author(s)
      Xiaoyu Li, Masahiko Ito, Haruyo Aoyagi, Asako Murayama, Hideki Aizaki, Masayoshi Fukasawa, Takanobu Kato, Takaji Wakita, Tetsuro Suzuki
    • Journal Title

      Int J Mol Sci

      Volume: 23 Issue: 15 Pages: 8711-8711

    • DOI

      10.3390/ijms23158711

    • Related Report
      2022 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Virus-like particles with FLAG-tagged envelope protein as a tetravalent dengue vaccine candidate2021

    • Author(s)
      Imagawa T, Ito M, Matsuda M, Nakashima K, Tokunaga Y, Ohta I, Li TC, Suzuki R, Suzuki T.
    • Journal Title

      Sci Rep

      Volume: 11 Issue: 1 Pages: 17542-17542

    • DOI

      10.1038/s41598-021-97038-4

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Dysregulation of intracellular pH is a cause of impaired capacitation in Slc22a14-deficient mice2021

    • Author(s)
      Ito M, Unou M, Higuchi T, So S, Ito M, Yogo K.
    • Journal Title

      Reproduction

      Volume: 163 Issue: 1 Pages: 23-32

    • DOI

      10.1530/rep-21-0135

    • NAID

      120007166730

    • Related Report
      2021 Research-status Report
    • Peer Reviewed
  • [Journal Article] MafF is an antiviral host factor that suppresses transcription from Hepatitis B Virus core promoter2021

    • Author(s)
      Ibrahim Marwa K.、Abdelhafez Tawfeek H.、Takeuchi Junko S.、Wakae Kosho、Sugiyama Masaya、Tsuge Masataka、Ito Masahiko、Watashi Koichi、El Kassas Mohamed、Kato Takanobu、Murayama Asako、Suzuki Tetsuro、Chayama Kazuaki、Shimotohno Kunitada、Muramatsu Masamichi、Aly Hussein H.、Wakita Takaji
    • Journal Title

      Journal of Virology

      Volume: 「-」 Issue: 15

    • DOI

      10.1128/jvi.00767-21

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Presentation] PLA2G4C induced by HCV infection is involved in the accumulation of lipid droplets via the inhibition of lipolysis2023

    • Author(s)
      Masahiko Ito, Masayoshi Fukasawa, Michinori Kohara, Tetsuro Suzuki.
    • Organizer
      29th International Symposium on Hepatitis C Virus and Related Viruses
    • Related Report
      2023 Annual Research Report
    • Int'l Joint Research
  • [Presentation] PLA2G4C induced by HCV infection is involved in the accumulation of lipid droplets via the inhibition of lipolysis2023

    • Author(s)
      Masahiko Ito, Masayoshi Fukasawa, Michinori Kohara, Tetsuro Suzuki.
    • Organizer
      第70回日本ウイルス学会学術集会
    • Related Report
      2023 Annual Research Report
  • [Presentation] Genome-wide CRISPR/Cas9 library screening identified HPSE2 as an inhibitor for HBV attachment2023

    • Author(s)
      Masahiko Ito, Hironori Nishitsuji, Kunitada Shimotohno, Tetsuro Suzuki.
    • Organizer
      2023 International HBV meeting
    • Related Report
      2023 Annual Research Report
    • Int'l Joint Research
  • [Presentation] SET suppresses HBV cccDNA formation mediated by histone H2AX2022

    • Author(s)
      Masahiko Ito, Tetsuro Suzuki
    • Organizer
      2022 International HBV meeting
    • Related Report
      2022 Research-status Report
    • Int'l Joint Research
  • [Presentation] cccDNA形成およびHBV再活性化におけるSETの役割2022

    • Author(s)
      伊藤昌彦, 鈴木哲朗
    • Organizer
      第69回日本ウイルス学会学術集会
    • Related Report
      2022 Research-status Report
  • [Presentation] ヒストンシャペロンSETを介したB型肝炎ウイルスゲノムcccDNA調節機構2021

    • Author(s)
      伊藤昌彦, 鈴木哲朗
    • Organizer
      第57回日本肝臓学会
    • Related Report
      2021 Research-status Report
  • [Presentation] Regulation mechanism of HBV cccDNA formation via histone chaperone SET/Template-activating factor2021

    • Author(s)
      Ito M, Suzuki T.
    • Organizer
      HBV2021
    • Related Report
      2021 Research-status Report
    • Int'l Joint Research
  • [Presentation] Nucleosome assembly proteins SET/TAF-I and H2AX regulate HBV cccDNA formation2021

    • Author(s)
      伊藤昌彦, 鈴木哲朗
    • Organizer
      第68回日本ウイルス学会
    • Related Report
      2021 Research-status Report

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Published: 2021-04-28   Modified: 2025-01-30  

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